Somatostatin (SRIF) is a tetradecapeptide that inhibits numerous endocrine and exocrine secretory functions. Almost all gut hormones that have been studied are inhibited by SRIF, including insulin, PP, glucagon, gastrin, secretin, GIP, and motilin (330). In addition to inhibition of the endocrine secretions, SRIF has direct effects on a number of target organs (331). For example, it is a potent inhibitor of basal and PG-stimulated gastric acid secretion. It also has marked effects on GI transit time, intestinal motility, and absorption of nutrients from the small intestine. The major effect in the small intestine appears to be a delay in the absorption of fat and reduced absorption of calcium.

The salient features of the somatostatinoma syndrome are diabetes, diarrhea/steatorrhea, gallbladder disease, hypochlorhydria, and weight loss (332-334). The first cases of the somatostatinoma syndrome were reported in 1977 by Ganda and colleagues (332). We have examined the cases reported since 1977 and describe here the features now recognized to be a part of the syndrome. For convenience, we have divided the cases into those arising from the pancreas, the intestine, and extrapancreatic tumors. It appears that the syndrome differs among tumors arising from the pancreas and the intestine or extrapancreatic sites. Therefore, these will be considered separately.

Clinical Features

Most patients were between 40 and 60 years of age. There is a 2:1 ratio of female to male patients, which contrasts with the equal sex incidence for other islet cell tumors (335).

Plasma Somatostatin-Like Immunoreactivity (SLI)

The mean SLI concentration in patients with pancreatic somatostatinoma was 50 times higher than normal (range, 1–250 times). Intestinal somatostatinomas, however, had only slightly elevated or normal SLI concentrations.

Diabetes Mellitus and Hypoglycemia

Seventy-five percent of patients with pancreatic tumors had diabetes mellitus. In contrast, diabetes occurred only in 11% of patients with intestinal tumors. In all instances, the diabetes was relatively mild and could be controlled with diet and/or oral hypoglycemic agents or with small doses of insulin. It is not clear, however, whether the differential inhibition of insulin and diabetogenic hormones can explain the usually mild degree of diabetes and the rarity of ketoacidosis in patients with somatostatinoma. Replacement of functional islet cell tissue by pancreatic tumor may be another reason for the development of diabetes in most patients with pancreatic somatostatinoma, contrasting with the low incidence in patients with intestinal tumors. These tumors usually are large and therefore destroy substantial portions of the pancreas.

Gallbladder Disease

Fifty-nine percent of patients with pancreatic tumors and 27% of patients with intestinal tumors had gallbladder disease. The high incidence of gallbladder disease in patients with somatostatinoma and the absence of such an association in any other islet cell tumor suggest a causal relationship between gallbladder disease and somatostatinoma. Infusion of somatostatin into normal human subjects has been shown to inhibit gallbladder emptying,(331;336) suggesting that somatostatin-mediated inhibition of gallbladder emptying may cause the observed high rate of gallbladder disease in patients with somatostatinoma. This thesis is supported by the observation of massively dilated gallbladders without stones or other pathology (337;338) in patients with somatostatin-secreting tumors.

Diarrhea and Steatorrhea

Diarrhea consisting of 3 to 10 frequently foul-smelling stools per day and/or steatorrhea from 20 to 76 g of fat per 24 hours is common in patients with pancreatic somatostatinoma. This could result from the effects of high levels of somatostatin within the pancreas, serving as a paracrine mediator to inhibit exocrine secretion or, alternatively, from the somatostatinoma’s causing duct obstruction. In some cases, the severity of diarrhea and steatorrhea parallels the course of the disease, worsening as the tumor advances and metastatic disease spreads, and improving after tumor resection. Somatostatin has been shown to inhibit the pancreatic secretion of proteolytic enzymes, water, bicarbonate, (339) and gallbladder motility (340). In addition, it inhibits the absorption of lipids (341). All but one patient with diarrhea and steatorrhea had high plasma somatostatin concentrations. The rarity of diarrhea and/or steatorrhea in patients with intestinal somatostatinomas may result from the lower SLI levels.

Hypochlorhydria

Infusion of somatostatin has been shown to inhibit gastric acid secretion in human subjects (342). Thus, hypochlorhydria in patients with somatostatinoma in the absence of gastric mucosal abnormalities likely results from elevated somatostatin concentrations. Basal and stimulated acid secretion was inhibited in 87% of patients with pancreatic tumors tested but in only 12% of patients with intestinal tumors.

Weight Loss

Weight loss ranging from 9 to 21 kg over several months occurred in one-third of patients with pancreatic tumors and one-fifth of patients with intestinal tumors. The weight loss may relate to malabsorption and diarrhea, but in small intestinal tumors, anorexia, abdominal pain, and yet unexplained reasons may be relevant.

Associated Endocrine Disorders

Of great interest is the presence of café-au-lait spots, neurofibromatosis, and paroxysmal hypertension in patients with intestinal tumors. Thus, approximately 50% of all patients have other endocrinopathies in addition to their somatostatinoma. Occurrence of MEN-1 has been recognized in patients with islet cell tumors, and MEN-2 or -3 syndromes are present in association with pheochromocytomas and neurofibromatosis, respectively. It seems that an additional dimension of the duct associated tumors is MEN-2. Secretion of different hormones by the same islet cell tumor, sometimes resulting in two distinct clinical disorders, is now being recognized with increasing frequency(343). These possibilities should be considered during endocrine work-ups of patients with islet cell tumors and their relatives.

Tumor Location

Of the reported primary tumors, 60% were found in the pancreas and 40% in the duodenum or jejunum. Of the pancreatic tumors, 50% were located in the head, and 25% in the tail, and the remaining tumors either infiltrated the whole pancreas or were found in the body. Regarding extrapancreatic locations, approximately 50% originate in the duodenum, approximately 50% originate in the ampulla, and, rarely, one is found in the jejunum. Thus, approximately 60% of somatostatinomas originate in the upper intestinal tract, which probably is a consequence of the relatively large number of D cells in this region.

Tumor Size

Somatostatinomas tend to be large, similar to glucagonomas,(344) but unlike insulinomas and gastrinomas, which, as a rule, are small (345-347). Within the intestine, tumors have tended to be smaller. Symptoms associated with somatostatinomas and glucagonomas are less pronounced and probably do not develop until very high blood levels of the respective hormones have been attained. As a result, somatostatinomas and glucagonomas are likely to be diagnosed later.

Incidence of Malignancy

Eighty percent of patients with pancreatic somatostatinomas were metastatic at diagnosis, and 50% with intestinal tumors had evidence of metastatic disease. Metastasis to the liver is most frequent, and regional lymph node involvement and metastases to bone are less so. Thus, in approximately 70% of cases, metatastic disease is present at diagnosis. This is similar to the high incidence of malignancy in glucagonoma (345) and in gastrinoma,(346) but it is distinctly different from the low incidence of malignant insulinoma (347). The high prevalence of metastatic disease in somatostatinoma also may be a consequence of late diagnosis but apparently is not dependent on the tissue of origin.

Microscopic Appearance

On light microscopy, most tumors appear to be well-differentiated islet cell or carcinoid-type tumors. Some show a mixed picture, consisting of separate zones of differentiated and anaplastic cells. In the differentiated areas, cells are arranged in lobular or acinar patterns that are separated by fibrovascular stroma. Less well-differentiated areas consist of sheets of cells interrupted by fibrous septa.

Diffuse positive immunoreactivity for somatostatin usually is found, which contrasts with the rarity of somatostatin-positive cells in gastrinomas and other tumors. There is a unique occurrence of psammoma bodies in somatostatinomas localized within the duodenum. In addition, there is abundant immunologic evidence for the presence of cells containing insulin, calcitonin, gastrin and VIP, ACTH, prostaglandin E2, and SP. In tumors with multiple hormones, however, SLI-containing cells represent the large majority of all cells containing hormones detected by immunopathology.

Somatostatin-Containing Tumors Outside the GI Tract

Somatostatin has been found in many tissues outside the GI tract. Prominent among those are the hypothalamic and extrahypothalamic regions of the brain, the peripheral nervous system (including the sympathetic adrenergic ganglia), and the C cells of the thyroid gland. Not surprisingly, therefore, high concentrations of somatostatin have been found in tumors originating from these tissues. Sano and colleagues (348) and Saito and colleagues (349) reported seven patients with medullary carcinoma of the thyroid (MTC) who had high basal plasma SLI concentrations and high tumor SLI concentrations. Roos and colleagues (350) reported elevated plasma SLI concentrations in three of seven patients with MTC and high tissue SLI concentrations in three of five MTC tumors. Some, but not all, of these patients exhibited the clinical somatostatinoma syndrome.

Elevated plasma SLI concentrations also have been reported in patients with small cell lung cancer (350). One case of metastatic bronchial oat cell carcinoma caused Cushing’s syndrome, diabetes, diarrhea, steatorrhea, anemia, and weight loss and had a plasma SLI concentration 20 times greater than normal (351). A patient with a bronchogenic carcinoma presenting with diabetic ketoacidosis and high levels of SLI (> 5,000 pg/mL) has been reported (352). Pheochromocytomas (343;353) and catecholamine-producing extra-adrenal paragangliomas (350) are other examples of endocrine tumors producing and secreting somatostatin in addition to other hormonally active substances. One-quarter of 37 patients with pheochromocytomas had elevated SLI levels (350).

Diagnosis

In the reported series cited, somatostatinomas often were found more or less accidentally. In most cases, the tumors were found either during exploratory laparotomy or upper GI radiographic studies, CT, or ultrasound, or endoscopy performed because of various symptoms, including unexplained abdominal pain, melena, hematemesis, persistent diarrhea, or in search of insulinomas or ACTH-secreting tumors. Once found, the tumors were identified as somatostatinoma by the demonstration of elevated tissue concentrations of SLI and/or prevalence of D cells by immunocytochemistry or demonstration of elevated plasma SLI concentrations. Thus, events leading to the diagnosis of somatostatinoma usually occur in reverse order. In other islet cell tumors, the clinical symptoms and signs usually suggest the diagnosis, which then is established by demonstration of diagnostically elevated blood hormone levels, following which efforts are undertaken to localize the tumors. It can be expected that the same sequence of diagnostic procedures will be followed in the future for the diagnosis of somatostatinoma, mainly for two reasons: (a) the increasing familiarity of physicians with the clinical somatostatinoma syndrome (this symptom complex, although not pathognomonic, is nevertheless sufficiently characteristic of somatostatinoma to suggest the correct diagnosis) and (b) the greater availability of reliable radioimmunoassays for the determination of SLI in blood has increased the yield. Presently, these assays are complicated by the need for cumbersome extraction procedures and are not readily available. (Assay available at Inter Science Institute-800-255-2873). It should be recognized, however, that the syndrome is rare. Of 1,199 cases screened for somatostatinoma at the University of Michigan between 1982 and 1986, only 8 cases had diagnostic serum levels.

The diagnosis of somatostatinoma at a time when blood SLI concentrations are normal or only marginally elevated, requires reliable provocative tests. Increased plasma SLI concentrations have been reported after intravenous infusion of tolbutamide and arginine, and decreased SLI concentrations have been observed after intravenous infusion of diazoxide. Arginine is a well-established stimulant for normal D cells and thus is unlikely to differentiate between normal and supranormal somatostatin secretion. The same may be true for diazoxide, which has been shown to decrease SLI secretion from normal dog pancreas as well as in patients with somatostatinoma (354). Tolbutamide stimulates SLI release from normal dog and rat pancreas,(339;340;354) but no change was found in the circulating SLI concentrations of three normal human subjects after intravenous injection of 1 g of tolbutamide (355). Therefore, at present, tolbutamide appears to be a candidate for a provocative agent in the diagnosis of somatostatinoma, but its reliability must be established in a greater number of patients and controls. Until then, it may be necessary to measure plasma SLI concentrations during routine work-ups for postprandial dyspepsia and gallbladder disorders, (333) for diabetes in patients without a family history, and for unexplained steatorrhea as these findings can be early signs of somatostatinomas.

Treatment of Somatostatinomas

Forty percent of patients with somatostatinomas died at intervals ranging from 1 week to 14 months after diagnosis, whereas 60% of patients were alive from 6 months to 5 years after diagnosis. Thus, the syndrome is associated with a high malignant potential, and it is important to be aggressive in management and to attempt to remove all tumor tissue in benign cases. For patients in whom metastases already have occurred at diagnosis, bulk reduction may be justified, if feasible. The optimal form of chemotherapy remains to be determined.